In response to the Request for Application (AT-01-004) released by NCCAM, we are proposing a multi-center randomized clinical trial (Trial to Assess Chelation Therapy [TACT]) in 1600 patients age 50 or older comparing 40 infusions of the standard chelation solution recommended by the American College for Advancement in Medicine versus 40 infusions of placebo. Chelation therapy, as practiced in the community, also includes the use of high dose antioxidant vitamin and mineral supplements. Thus, any clinical benefit of chelation therapy may be due either to the effect of EDTA chelation, or high dose supplements, or both. Therefore, we are further proposing a 2X2 factorial design to independently test the effects of a high-dose supplementation, versus a low dose regimen to simply replace chelation-related losses. The primary endpoint of this trial will be a composite of all cause mortality, myocardial infarction, stroke, hospitalization for angina and hospitalization for congestive heart failure. This primary endpoint is consistent with the RFA. TACT will have over 90 percent power to detect a 25 percent reduction, and over 80 percent power to detect a 20 percent reduction in this primary endpoint. Major secondary endpoints will include (1) a combined endpoint of cardiac death, or nonfatal myocardial infarction, or nonfatal stroke; (2) the individual components of the primary endpoint; (3) coronary revascularization; (4) safety of the interventions including indices of renal, hepatic, and hematological function, as suggested by the RFA; (5) health-related quality-of-life; (6) cost and cost-effectiveness, as suggested by the RFA; (7) brachial artery flow-mediated endothelial function, as suggested by the RFA; (8) plasma markers of oxidative stress and anti-oxidant protection, as suggested by the RFA; and (9) plasma markers of endothelial activation and inflammation, as suggested by the RFA. The results of TACT will provide either a significant positive result or an informative null result upon which rational clinical decision-making and health policy can be based.